Ziprasidone is known compound having the structure:
It is disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925, both of which are herein incorporated by reference in their entirety, has utility as a neuroleptic, and is thus useful, inter alia, as an antipsychotic. It is typically administered orally as the hydrochloride and addition salt, ziprasidone hydrochloride monohydrate. The hydrochloride salt is advantageous in that it is a high permeability drug, a factor which favorably affects bioavailability. The hydrochloride salt, as well as other ziprasidone acid addition salts, does, however, possess relatively poor aqueous solubility, a factor which unfavorably affects bioavailability.
Difficult to wet pharmaceutically acceptable compounds can be problematic in the pharmaceutical arts from a formulations perspective. For example, ziprasidone hydrochloride, in addition to having low solubility, is difficult to wet with an aqueous medium, and thereby presents special problems from the standpoint of trying to form an aqueous suspension. In the discussion which follows, ziprasidone hydrochloride is discussed as an exemplary member of the class composed of ziprasidone free base and ziprasidone acid addition salts which are difficult to wet. The invention is not to be taken as being limited to ziprasidone hydrochloride, however.
Owing to difficulties in wetting ziprasidone acid addition salts such as ziprasidone hydrochloride, the material is difficult to adequately suspend in an aqueous medium without having to resort to using long periods of high shear mixing. An ordinary laboratory homogenizer generally does not wet ziprasidone hydrochloride without being run for a very long time. Long blending periods almost inevitably lead to foaming and still yield poor results with drug aggregates still being visibly present, entrained in the foam. Thus, ziprasidone hydrochloride tends to float on the surface of water and other aqueous media and can be induced to form a suspension only with physical measures (high shear mixing for long times) that are considered extreme.
An alternative mixing procedure comprises first adding only a small amount of water to the ziprasidone salt, followed by grinding to wet the bulk drug substance. This wets the mass sufficiently so that it can be suspended in water. This procedure is still disadvantageous however in that it is difficult to scale up. Moreover, once ziprasidone hydrochloride has been induced to form an aqueous suspension in this fashion, an additional challenge is the prevention or retarding of rapid re-setting, which occurs relatively quickly with ziprasidone hydrochloride, generally within an hour or so, depending on the particle size. Settling can be particularly problematic for a pharmaceutical suspension since the suspension must be adequately re-suspended to ensure that an adequate dosage is administered to the patient.
One approach to improving the anti-setting properties of a suspension is to use a viscosity agent such as any of the natural gums or cellulosics, such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC) to increase viscosity, and thereby retard the rate of re-setting of wetted particles in the suspension. Such an approach has been found to be problematic in the case of ziprasidone hydrochloride since, once a viscosity agent has been added, when the ziprasidone hydrochloride eventually settles, it tends to form a thin cake which sits on the bottom and can be very difficult to break up and to re-suspend. Such caking is facilitated by temperature fluctuations and by vibrations such as those which occur during normal handling and transportation.
Further, in the specific case of ziprasidone acid addition salts, such salts generally exhibit a very bitter taste, the degree of bitterness increasing with increasing solubility of the particular salt. Sugars, with or without the presence of other sweetening and/or flavoring agents, are generally insufficient to mask the bitter taste. Adjusting the pH to form the less soluble, hence less bitter, free base, is an option for decreasing bitterness. However, such adjustment can lead to changes in particle size if very careful and continuous control is not maintained. Substantial changes in particle size can, in turn, undesirably lead to changes in bioavailability.
Thus, a suspension comprising ziprasidone free base or ziprasidone hydrochloride (or other pharmaceutically acceptable ziprasidone addition salt) which maintains an improved shelf life (i.e., which maintains a longer period of suspension prior to re-settling) and which is easily re-suspendible would represent a valuable addition to the formulations arts. In the particular case of a suspension of a ziprasidone acid addition salt, a suspension with improved taste would be a further valuable addition.